The main objective of the proposed research is to learn more about the mechanism(s) of murine skin carcinogenesis in the hope that the information will provide clues to the mode of origin of cancer in humans. We will use the naturally occurring cellular mosaicism based upon X-chromosome inactivation to study sequentially the initial events, the process leading to formation of papillomas and the progression to carcinomas in a murine multistage skin carcinogenesis model. We will attempt to determine the number of cells from which papillomas and carcinomas arise. In addition, the following specific questions will be addressed: Do invasive epidermoid carcinomas arise by sequential growth of benign papillomas? Are there any differences in the mechanism of skin tumor development induced by an initiation-promotion regimen and by complete carcinogens? Are carcinogen-initiated cells heterogeneous and do different promoters and carcinogens affect different subsets of altered cells? How do inhibitors affect the cellular origin of premalignant and malignant lesions? This information will provide an insight into the mechanism of initiation and promotion during carcinogenesis. Hopefully, understanding this mechanism will indicate the relevance of the promotion process to multistep carcinogenesis in humans.